P510: PREDICTORS OF RESPONSE AND OUTCOME IN PATIENTS WITH REFRACTORY/RELAPSED ACUTE MYELOID LEUKEMIA RECEIVING VENETOCLAX WITH NON-INTENSIVE CHEMOTHERAPY
Authors: Katja Krüger, Martin Wichmann, Razif Gabdoulline, Katharina Götze, Krischan Braitsch, Franziska Modemann, Walter Fiedler, Arne Trummer, Jürgen Krauter, Stephan Kaun, Susanne Rotermund, Andreas Voß, Gudrun Goehring, Yvonne Behrens, Felicitas Thol, Matthias Eder, Gernot Beutel, Michael Stadler, Michael Heuser, Rabia Shahswar
Journal: HemaSphere (2023)

Background: Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical condition with limited treatment options and dismal prognosis. In newly diagnosed AML patients (pts), a modified risk stratification based on the mutational status of four genes (FLT3-ITD, KRAS, NRAS and TP53) indicated distinct benefit from treatment with azacitidine and venetoclax (Döhner et al. ASH 2022). However, the role of venetoclax (VEN) in R/R AML is not well defined yet and predictors of response are unclear. Aims: To identify predictors of response and survival of off-label VEN+non-intensive therapy in pts with R/R AML reported to the venetoclax registry (NCT03662724). Methods: We retrospectively analyzed clinical characteristics and outcomes of R/R AML pts treated with VEN-based non-intensive treatment-regimens between February 2017 and February 2023. Cytogenetic and molecular studies were performed at the time of refractory or relapsed AML by conventional karyotyping and next-generation sequencing. Mutations associated with myeloid leukemias were detected using a custom myeloid sequencing panel, which included 48 genes. VEN was combined with either azacitidine, decitabine or LDAC. The overall response rate (ORR) was defined by complete remission (CR) + CR with incomplete hematologic recovery (CRi) + morphologic leukemia-free state (MLFS). Data cut-off was February 21, 2023. Results: One-hundred-sixty-three pts with either relapsed (n=67, 41%) or refractory (n=81, 50%; missing 9%) AML and a median age of 70 years (range, 24-86) were included in our analysis. Prior treatment lines included intensive chemotherapy (61%), HMA treatment (58%) and allogeneic transplantation (33%). ELN2017 risk was intermediate and adverse in 31% and 55% of pts in this high-risk cohort. Forty-five pts (28%) had complex cytogenetics and seventeen pts (10%) had extramedullary disease manifestation. In total, 29 genes were found mutated in ≥5 pts. The overall response rate (ORR) was 44% (n=77), including 38% of pts achieving CR/CRi and 6% MLFS. After a median follow-up of 25.9 months (mo), median overall survival (OS) and median event-free survival (EFS) was 8.4 mo (95% CI, 5.7-11.04) and 4.8 mo (95% CI, 3.6-6), respectively. Clinical predictors of survival included age above the median age (≥70 years vs. <70 years 6.4 vs. 10 mo, p=0.07), HMA pretreatment (pretreatment vs. no pretreatment 6.0 vs. 10.2 mo, p=0.02), extramedullary disease manifestation (present vs. absent 5.0 vs. 9.3 mo, p=0.01). A modified risk model was constructed based on the mutational status of nine genes that were associated with survival. Pts were classified into three risk groups with significantly different OS based on mutated STAG2, BCOR or SF3B1 (favorable risk; median OS 17.5 mo), mutated TP53, any FLT3, CBL, PTPN11 or NF1 mutation (adverse risk; median OS 4.6 mo), and all other pts (intermediate risk; median OS 9.6 mo; p<0.001) (Figure 1). This risk score was also prognostic for EFS and ORR. In multivariate analysis the genetic R/R AML VEN risk model (p<0.001), extramedullary disease (p=0.02), and HMA pretreatment (p=0.01) remained significant predictors of inferior survival. Summary/Conclusion: This real-world analysis comprising a large cohort of R/R AML pts treated with VEN-based non-intensive therapies identifies the presence of extramedullary disease and HMA pretreatment as clinical predictors of inferior survival. Further, our data suggest a novel prognostic risk classification based on the mutational status of nine genes with significant OS, EFS and ORR distinction. The genetic R/R AML VEN risk score requires independent validation. Figure 1Keywords: Real world data, Molecular markers, Venetoclax, Acute myeloid leukemia